Abstract:

Human protein-based biomaterials facilitate the development of preclinical models that integrate predictive value and ethical responsibility. Metatissue uses decellularized extracellular matrix from placenta samples and human blood to create tunable, xeno-free substrates for 3D cell culture, minimizing the reliance on animal models and accelerating translational research.

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Abstract:

Human platelet lysates (hPL) have been explored in regenerative medicine as a source of growth factors and other bioactive proteins. However, their poor mechanical properties often fail to recapitulate hard tissues such as bone or bone-to-cartilage interfaces. To address this challenge, mechanically reinforced nanocomposite hydrogels were developed, by integrating functionalized nano-hydroxyapatite (nHAp-MA) within a bioactive organic matrix through a tailored interfacial strategy. This strategy enabled achieving an injectable hPL solution through ECD/NHS chemistry which could be later photocrosslinked in situ, taking advantage of the photocurable moieties of both the organic and inorganic components. Rheological data revealed an increase in the elastic modulus in two moments: the first after nHAp incorporation and the second after photocrosslinking. Enhanced mechanical properties were obtained in the functionalized nanocomposite materials when used at high concentrations. The increase in the particle content from 1 to 5 % highlighted the importance of particle functionalization to maintain mechanical stability. These nanocomposite hydrogels also presented controlled protein release over time, and great biological performance both in vitro and in vivo. By playing with the quantity of chemical crosslinker and nanoparticle content, tunable properties were achieved in tough and injectable human-based biomaterials, promising for a range of biomedical applications.

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Abstract:

Xanthan gum (XG) has performed far better than other polysaccharides for industrial purposes, e.g., food, pharmaceutical, and cosmetic applications, due to its outstanding thickening effect, pseudoplastic rheological properties, and non-toxicity. However, there is no crosslinking strategy available for non-modified XG that allows its sole use within cells for biomedical engineering applications. Here, we established this crosslinking strategy while processing it via additive manufacturing techniques. The suitability of divalent (Ca2+, Mg2+, and Fe2+) and trivalent (Al3+ and Fe3+) ions was evaluated by an in situ rheological assessment. Fe3+ demonstrated a high affinity to XG by forming a stable crosslinking effect, and the baseline XG−Fe3+ hydrogel exhibited outstanding printability and high culture stability (60 days). Although XG−Fe3+ demonstrated high biocompatibility for hMSCs with sustained cytocompatible iron release, these cell-laden constructs are inert. Envisioning biological functionality, we blended human methacryloyl platelet lysates (hPLMA) with XG−Fe3+ and either used inert XG−Fe3+ or bioactive cell-adhesive XG−Fe3+−PLMA, resulting in a 10-fold increase in strength compared to non-crosslinked XG. Remarkably, whether inert or bioactive, hydrogels proved to be mechanically tunable (from ∼3 to 203 kPa), ideal for tissue engineering applications. Later, we expanded the XG−Fe3+ role to a delivery system using magnetic nanoparticles (MNPs), and magnetically responsive scaffolds were obtained (XG−Fe3+−MNP). Finally, to explore the convergence of 3D printing and melt electrowriting (MEW), polycaprolactone (PCL) was included to obtain hybrid scaffolds (XG−PLMA−PCL). Our findings present a novel XG−Fe3+ hydrogel with remarkable versatility as a natural, mechanically tunable, bioactive, and magnetic- responsive system for sole or hybrid use. This unusual set of capabilities meets the current demand for developing tailored hydrogels for complex biomedical engineering applications.

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Abstract:

The development of effective cell delivery therapies faces challenges regarding cell viability and retention after injection. Hydrogel-based materials, designed to mimic extracellular matrix components for cell protection during injection and to enhance local availability, often rely on animal-derived components that raise immunogenicity concerns. Alternatively, those employing polysaccharides and synthetic polymers may exhibit suboptimal cell adhesive properties. This study showcases the development of injectable human protein-derived cell carrier microgels made from methacryloyl platelet lysates. These microgels sustain cell viability by providing an enriched and cost-effective environment of growth factors and proteins while promoting the outward migration of mesenchymal stem cells through controlled enzyme-mediated degradation. Employing a solvent-free and reproducible method using superhydrophobic surfaces, human-derived microgels are successfully fabricated via light irradiation, with sizes adjustable by varying droplet volume. Additionally, the incorporation of collagenase facilitates enzyme-mediated cell migration without compromising viability. Injectability tests confirm that microgel administration preserves both size and morphology, and their effectiveness in filling irregular defects in a porcine tissue highlights their suitability for therapeutic applications. Ultimately, these microgels can be modified to include magnetic nanoparticles, enabling spatial control and fixation using an external magnetic field, and potential imaging capabilities, positioning them as promising candidates for personalized cell therapies.

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Abstract:

Exploring the natural availability and intrinsic bioactivity of blood-derived proteins opens new avenues for fabricating bioactive and patient-specific solutions for biomedical applications. Despite their several advantages, their use as inks for 3D printing is limited due to suboptimal rheological properties. To address this, we propose a dual-step strategy based on the initial generation of blood protein-based bulk hydrogels encompassing pristine and photo-responsive protein mixtures to allow their mechanical granularization followed by jamming, establishing injectable and printable granular inks. In this study, two globular-based protein matrices—human platelet lysates (PL) and bovine serum albumin (BSA)—were used as granular inks for 3D printing. We hypothesize that nozzle jamming—in contrast to the typically employed centrifugal jamming—would render optimized results for the granular protein inks’ processability. Printability was evaluated in filaments, scaffold grids, and convoluted structures. Taking advantage of the previously introduced photocurable moieties, post-printing photocrosslinking was used for the annealing of the microgels, leading to increased scaffold mechanical stability and robustness. The nozzle jamming methodology imparted the best print performance and reproducibility, where PLMA-based inks outperformed the BSAMA-based. In addition, the microgel granular constructs allowed primary human-derived adipose stem cells to adhere and proliferate, whereas the PLMA-based ink demonstrated higher cell affinity and enhanced biological performance. We further demonstrated that bioinks could be developed from PLMA-based inks, showcasing high viability without compromising 3D printing performance. Overall, this study gives clear insights into the importance of the jamming process as well as the granularization outcome requirements for the obtention of highly reproducible granular inks for 3D printing.

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